Subthalamic Nucleus Deep Brain Stimulation: Basic Concepts and Novel Perspectives

Abstract

Over the last decades, extensive basic and clinical knowledge has been acquired on the use of subthalamic nucleus (STN) deep brain stimulation (DBS) for Parkinson's disease (PD). It is now clear that mechanisms involved in the effects of this therapy are far more complex than previously anticipated. At frequencies commonly used in clinical practice, neural elements may be excited or inhibited and novel dynamic states of equilibrium are reached. Electrode contacts used for chronic DBS in PD are placed near the dorsal border of the nucleus, a highly cellular region. DBS may thus exert its effects by modulating these cells, hyperdirect projections from motor cortical areas, afferent and efferent fibers to the motor STN. Advancements in neuroimaging techniques may allow us to identify these structures optimizing surgical targeting. In this review, we provide an update on mechanisms and the neural elements modulated by STN DBS.

Keywords: anatomy; deep brain stimulation; mechanisms; neuroimaging; physiology; plasticity; subthalamic nucleus.

Figure 1.

STN and the tripartite model. Intrinsic organization of the STN, basal ganglia structures, and cortical regions according to the tripartite functional subdivision. The motor circuit (blue) includes motor cortical areas (primary motor cortex, supplementary motor cortex, premotor cortex, and portions of the somatosensory dorsal parietal cortex), the dorsolateral portion of the postcommissural putamen, the lateral two-thirds of the globus pallidus (GPe and GPi), and a small portion of the substantia nigra (SNr). In the STN, motor regions comprise dorsal-lateral aspects of the rostrocaudal third of the nucleus (Hamani et al., 2004). Associative circuits (purple) comprise associative cortical regions, most of the caudate nucleus, the putamen rostral to the anterior commissure, the dorsal aspect of the medial third of the globus pallidus (GPe and GPi) and most of the substantia nigra. Associative STN regions may be found in ventral-lateral-rostral portions of the nucleus (Hamani et al., 2004). Limbic circuits (gray) are comprised of limbic cortical areas (e.g., orbitofrontal and the anterior cingulum), the nucleus accumbens and the most rostral portions of the striatum, the subcommissural ventral pallidum (VP), small limbic regions in the ventral portion of the medial third of the globus pallidus (GPe and GPi), the medial tip of the substantia nigra, and the ventral tegmental area. The limbic STN lies in mediorostral portions of the nucleus (Hamani et al., 2004). Arrows represent some of the most important connections between structures. D, dorsal; L, lateral; M, medial; V, ventral. We note that this schematic diagram largely represents structures in two planes with the anteroposterior depiction often lacking. This is the main reason for the superposition of colors representing motor, associative and limbic regions. Parts of this figure were modified and reprinted with permission from Hamani et al. (2004); Krack et al. (2010).

Figure 2.

Anatomic aspects of the STN. Principal brain structures surrounding the STN. FF, fields of Forel; FS, subthalamic fascicle; H1, H1 field of Forel (thalamic fasciculus); H2, H2 field of Forel; IC, internal capsule; ML, medial lemniscus; PPN, pedunculopontine nucleus; Put, putamen; SN, substantia nigra; Thal, thalamus; ZI, zona incerta. Part of this figure was modified and reprinted with permission from Hamani et al. (2004).

Figure 3.

STN and pallidofugal fibers. Axial (A) and coronal (B) schematic representations of the AL (red) and LF (H2; blue), in relationship to the STN, in nonhuman primates. Note that both the tracts travel dorsal to the most anterior aspect of the STN. A, The thalamic fasciculus is represented in green. ant, anterior; lat, lateral; sup, superior. Modified and reprinted with permission from Parent and Parent (2004).

Figure 4.

Histologic sections of the subthalamic nucelus (STN) region in individuals with no neurologic disorders stained for gallocyanin. A, Note the presence of high-density cellular regions near the borders of the nucleus (white arrow) and fibers inside its core (*). The dark arrow points to a vessel branching in the vicinity of the STN. B, Sagittal section (400-µm thickness) showing high-density neuronal clusters (white arrow) and a region largely comprised by capsular fibers (arrowhead) near the dorsal border of the STN. Magnified view is presented in the square above. C, Axial (horizontal) section (440-µm thickness) showing the anteromedial aspect of the STN in relation to the lateral hypothalamus (LH) and fornix (Fx). Black arrows denote subthalamic cell strands piercing the internal capsule and forming dissipated accessory cell groups (black open triangle) near the lateral hypothalamus. White open triangles represent the irregular boundary between STN cell clusters and capsular fibers. D, Coronal section (440-µm thickness) showing the STN region under dark-field illumination (RN, red nucleus). SNr, substantia nigra reticulata; SNc, substantia nigra compacta; ZI, zona incerta.

Figure 5.

Neural elements modulated by DBS delivered to the dorsal region of the motor subthalamic nucleus (STN) territory. A, Schematic representation of the STN showing potential fiber pathways modulated by DBS. Hyperdirect STN projections from motor cortical regions are depicted in blue. Pallidofugal fibers are depicted in red. B, Schematic representation of an STN neuron modulated by DBS. STN axons driven by stimulation would excite connected structures. Stimulation of STN afferents would potentially excite these projections, inducing complex effects. STN cells would be excited by stimulation of cortical and thalamic-STN projections (blue) and inhibited by stimulation of globus pallidus projections and appendages from local interneurons (red). Stimulation of brainstem-STN projections would modulate STN neuronal activity via different neurotransmitter systems (green). 5HT, serotonin; ACh, acetylcholine; CM, centromedian nucleus of the thalamus; DA, dopamine; GPe, globus pallidus externus; GPi, globus pallidus internus; LC, locus ceruleus; LDTg, laterodorsal tegmental area; NE, norepinephrine; PPN, pedunculopontine nucleus; SNc, substantia nigra compacta. Part of the figure was reprinted with permission from Hamani et al. (2004).

Figure 6.

Tractography based subdivision of the STN. A, CoronalT2∗-weighted images obtained at 7.0T, 3.0T, and 1.5T. B, Coronal images showing STN connectivity with limbic (red), associative (green), motor (blue), and remaining (yellow) cortical areas. C, Oblique view of the STN with a superposed DBS electrode and an active contact implanted in the motor territory. Reprinted with permission from Cho et al. (2010); Plantinga et al. (2014); Plantinga et al. (2016).